1. Field of the Invention
The invention relates to a type of novel 1,2,3,4-tetrahydroisoquinoline derivatives, and in particular, 1,2,3,4-tetrahydroisoquinoline derivatives useful for the treatment of Alzheimer's disease (AD), to processes for its preparation and pharmaceutical compositions containing the same.
2. Description of the Prior Art
Alzheimer's disease (AD) is a disease characterized in constant loss of nervous function due to death of brain nervous cells caused by deposition of non-hydrolytic toxic proteins in the brain. In 1906, Alois Alzheimer, a German neuropathologist, performed brain tissue dissection on a dead woman with serious dementia and had found some abnormal plaques and tangles of her nerve fibers in her brain tissue. In his study, it was found that these plaques consisted of non-soluble proteins and might result in inflammation and death of brain nerve cells. Alzheimer's disease was thus named after this pathologist's name.
Subjects of Alzheimer's disease primarily have nerve cells in brain cortex and hippocampus that have been damaged or died which result in gradual loss of their memory as well as dysfunctions in language and emotion. Incipient symptom is amnesia, daily behavior is marked by increasing loss of short-term memory, while long-term memory is comparatively not affected. Later stage symptoms consist of serious cognitive dysfunction, difficulty to adapt to social life, which result in problems of inability to understand conversation content, incapability to solve vital functions such as eating, drinking and the like, and finally, lead to paralysis. Alzheimer's disease itself is not lethal, and most such patients die due to accidents caused by dementia, long-term lying in bed, or other infections (e.g., septicemia, pneumonia, etc.) induced by reduction of immunity. The stages of Alzheimer's disease may last for about 1 to 25 years, and an AD patient may have an average life-span from diagnosis to death of about 8 to 10 years. Statistically, females are more likely to be affected than males, and prevalence rate of 11% occurs usually in population ages of more than 65 years old, and about 50% in more than 80 years old, and as such, it is also known as senile dementia.
One of the pathological characteristics of Alzheimer's disease is deposition of amyloid plaque in the brain. These plaques consist mainly of β amyloid-peptides (Aβ), β amyloid-peptides (Aβ) are not direct gene products, but products generated by various enzymatic cleavage of pre-formed amyloid precursor protein (APP). Amyloid precursor protein (APP) is a single transmembrane protein, and is associated with two degradation pathways: one of these comprising of producing soluble amyloid precursor protein α (sAPPα) by sequential cleavage with α-secretase and γ-secretase; the other pathway comprising of producing insoluble β amyloid-peptides (Aβ) by cleavage first with β-secretase followed with γ-secretase. In brain nerve cells of a patient with Alzheimer's disease, it is believed that the proteolytic process of amyloid precursor protein (APP) may pass mostly through a cleavage pathway with β-secretase and γ-secretase, and hence produce more insoluble βamyloid-peptides (Aβ). Since γ-secretase has various cleavage sites on amyloid precursor protein (APP), insoluble β amyloid-peptides (Aβ) of varying size may be produced. Among these Aβ, Aβ42 exhibits higher toxicity and tend to fibrillate into a polymer which deposit to form the core of a plaque and enable other types of β amyloid-peptides (Aβ) (mostly Aβ40) to deposit more easily over these plaques. At present it has been found that in brain of a patient of Alzheimer's disease, the proportion of Aβ42 in all Aβs is higher than that in a normal man.
From studies on cell level and in pharmacology, it has been found that γ-secretase is an aspartyl protease, and that, modulation with γ-secretase as the therapeutic target is considered to be a very important approach in the treatment of Alzheimer's disease. However, another approach for treatment of AD relates to the modulation on proteolytic process of α-secretase. Said proteolytic process comprises cleavage of amyloid precursor protein (APP) with α-secretase to produce soluble amyloid precursor protein α (sAPPα), which prevents indirectly the production of insoluble β amyloid-peptides (Aβ). In the present studies, it has been found that the proteolytic process of α-secretase may be modulated by mitogen-activated protein kinase (MAPK) pathway. MAPK pathway relates to a series of activation process for mitogen-activated protein kinase (MAPK) and extracellular signal-regulated protein kinase (ERK). Accordingly, how to modulate MAPK signaling cascade to influence further the proteolytic process of α-secretase constitutes a very important approach for the treatment of Alzheimer's disease.
Earlier development on medicament for treatment of Alzheimer's disease relied on symptom alleviation of Alzheimer's disease with drugs. The United States Food and Drug Administration (FDA) has approved four drugs for enhancing memory and retarding the progress of Alzheimer's disease. The first drug was the approved Tacrine (trade name: Cognex), which exhibited a number of side effects, including disadvantages of high hepato-toxicity, poor effect for enhancing memory and the like. Three other approved drugs were Donepezil (trade name: Aricept), Rivastigmine (trade name: Exelon), and galantamine (trade name: Reminyl), respectively. Said drugs had been proved to improve memory, and had little side effects. Among these, both of Tacrine and Donepezil inhibited degradation of acetylcholine by blocking the activity of cholinesterase. Both drugs could increase the content of acetylcholine in the brain so as to retard memory loss and help patients to perform daily life activities. These drugs could not cure Alzheimer's disease, but only mitigate symptom of Alzheimer's disease. In addition, these drugs were not effective for everyone, rather limited to be effective for early and immediate phase's patients of Alzheimer's disease. Therefore, it is still a medical bottleneck in the state of art for prevention and earlier diagnosis of Alzheimer's disease.
In view of the foregoing, the above-described approaches still have many disadvantages, and are not perfect designs and urgently need improvement.
The soluble form of APPα was found to possess potent neurotropic and neuroprotective activities against oxidative and excitotoxic insults. Further investigations indicated that rasagiline, a MAO-B inhibitor, and its carbamyl-containing derivative, TV-3326, regulate MEK-dependent APP processing in SH-SY5Y neuroblastoma and PC12 cells, which resulted in the stimulation of release of the neuroprotective sAPPα. Nevertheless, selegiline, a well-known selective MAO-B inhibitor for increasing the efficacy of levodopa therapy in the treatment of Parkinson's disease, also exerted neuroprotective effects in various preclinical models. These results suggested that a crucial role for MEK-dependent pathways may be involved in the enhancement of sAPPα release by selegiline and rasagiline. Taken together, the secretase-mediated proteolysis of APP can be subject to multiple levels of regulation by intracellular pathways and the ERK activation could play a pivotal role in shifting the APP processing to the α-secretase-initiated non-amyloidogenic pathway synergistically blocking γ-secretase-dependent Aβ production. Conversely, reduction of formidable Aβ production by interfering γ-secretase activity with enzyme-targeted inhibitors might shift the APP processing to the α-secretase-mediated pathways. Thus, control of Aβ production by direct or indirect modulation of γ-secretase activity on APP opens the approaches toward the treatment of Alzheimer's disease.
As such, in view of the above-described disadvantages derived from the conventional drugs used for Alzheimer's disease, the inventors had thought to improve and innovate, and finally, after studying intensively for many years, had developed 1,2,3,4-tetrahydroisoquinoline derivatives according to the invention, its preparation process and pharmaceutical composition containing the same.